scholarly journals Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer

2018 ◽  
Vol 51 (2) ◽  
pp. 610-629 ◽  
Author(s):  
Zhonghu Li ◽  
Yang Tao ◽  
Xiaoya Wang ◽  
Peng Jiang ◽  
Jie Li ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Ductal Adenocarcinoma ◽  
Mirna Microarray ◽  
Biological Assays ◽  
Exosomal Mirnas ◽  
Promote Cell Survival ◽  
Xenograft Models ◽  
Tumor Exosomes ◽  
Microarray Studies ◽  
Prognostic Maker

Background/Aims: MicroRNAs (miRNAs) or exosomes have recently been shown to play vital regulatory or communication roles in cancer biology. However, the roles and mechanisms of exosomal miRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. We aimed to investigate the detailed roles and mechanisms of tumor-generated exosomal miRNAs in progression of PDAC. Methods: miR-222 was identified by miRNA microarray studies in exosomes of PDAC cells, and further analyzed in plasma exosomes of PDAC patients. The regulatory mechanisms of miR-222 were explored by qRT-PCR, WB, dual-luciferase assays and immunofluorescence or confocal analysis. Other biological assays include transwell, xenograft models and so on. Results: miR-222 is significantly high in tumor exosomes or highly invasive PDAC cells. miR-222 could directly regulate p27 to promote cell invasion and proliferation. miR-222 could also activate AKT by inhibiting PPP2R2A expression, thus inducing p27 phosphorylation and cytoplasmic p27 expression to promote cell survival, invasion and metastasis. Expressions of miR-222 and p27 were significantly inversely correlated, and cytoplasmic p27, instead of nuclear p27, was associated with tumor malignancy. miR-222 could be transmitted between PDAC cells via exosome communication, and the exosomal miR-222 communication is functional. Plasma exosomal miR-222 in PDAC patients was high and significantly correlated to tumor size and TNM stage, and was an independent risk factor for PDAC patient survival. Conclusion: Tumor-generated exosomes could promote invasion and proliferation of neighboring tumor cells via miR-222 transmission, the plasma exosomal miR-222 plays important roles and may be a useful prognostic maker in PDAC.

scholarly journals The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Luisa Statello ◽  
Mohamad M Ali ◽  
Silke Reischl ◽  
Sagar Mahale ◽  
Subazini Thankaswamy Kosalai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Biology ◽  
Topoisomerase I ◽  
Cell Cycle Checkpoints ◽  
Topoisomerase 1 ◽  
Damage Response ◽  
Promote Cell Survival

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

scholarly journals LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xudong Huang ◽  
Ling Pan ◽  
Zhixiang Zuo ◽  
Mei Li ◽  
Lingxing Zeng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acid Synthesis ◽  
Ductal Adenocarcinoma ◽  
High Concentration ◽  
Metabolic Switch ◽  
Non Coding Rna ◽  
Xenograft Models ◽  
Transcription Factor Yy1 ◽  
Catabolic Process

AbstractThe molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.

scholarly journals Fibroblasts as a Biological Marker for Curative Resection in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (11) ◽  
pp. 3890 ◽  
Author(s):  
Eriko Katsuta ◽  
Omar M. Rashid ◽  
Kazuaki Takabe
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Curative Resection ◽  
Biological Marker ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Small Subset ◽  
Inverse Association ◽  
Anti Cancer

Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that intratumor fibroblasts contribute to curative resection and a better survival of PDAC. Utilizing a large, publicly available PDAC cohort, we found that fibroblast composition was associated with R0 curative resection. A high amount of fibroblasts in PDACs was significantly associated with a higher amount of mature vessels, but not with blood angiogenesis. A high amount of fibroblasts was also associated with a higher infiltration of anti-cancer immune cells, such as CD8+ T-cells and dendritic cells, together with higher inflammatory signaling, including IL2/STAT5 and IL6/JAK/STAT3 signaling. Further, the fibroblast composition was inversely associated with cancer cell composition in the bulk tumor, along with an inverse association with proliferative characteristics, such as MYC signaling and glycolysis. The patients with high-fibroblast PDACs showed an improved prognosis. In conclusion, we found that PDACs with high fibroblasts were associated with a higher R0 resection rate, resulting in a better prognosis. These findings may be due to less aggressive biology with a higher vascularity and anti-cancer immunity, and a low cancer cell component.

scholarly journals Exosomes and the Future of Immunotherapy in Pancreatic Cancer

2019 ◽  
Vol 20 (3) ◽  
pp. 567 ◽  
Author(s):  
Ines Batista ◽  
Sonia Melo
Keyword(s):  
Quality Of Life ◽  
Pancreatic Cancer ◽  
Tumor Stroma ◽  
Transport Proteins ◽  
Ductal Adenocarcinoma ◽  
Immunomodulatory Effects ◽  
Phenotypic Changes ◽  
Tumor Exosomes ◽  
Immunosuppressive Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, associated with a late diagnosis and a five-year survival rate of 8%. Currently available treatments fall short in improving the survival and quality of life of PDAC patients. The only possible curative option is still the surgical resection of the tumor. Exosomes are extracellular vesicles secreted by cells that transport proteins, lipids, and nucleic acids to other cells, triggering phenotypic changes in the recipient cells. Tumor cells often secrete increased amounts of exosomes. Tumor exosomes are now accepted as important players in the remodeling of PDAC tumor stroma, particularly in the establishment of an immunosuppressive microenvironment. This has sparked the interest in their usefulness as mediators of immunomodulatory effects for the treatment of PDAC. In fact, exosomes are now under study to understand their potential as nanocarriers to stimulate an immune response against cancer. This review highlights the latest findings regarding the function of exosomes in tumor-driven immunomodulation, and the challenges and advantages associated with the use of these vesicles to potentiate immunotherapy in PDAC.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

2018 ◽  
Vol 17 (4) ◽  
pp. 1016-1019 ◽  
Author(s):  
Chao Qu ◽  
Qing Wang ◽  
Zhiqiang Meng ◽  
Peng Wang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

scholarly journals Methodological aspects of creation of patient-derived tumor xenografts

2021 ◽  
Vol 102 (5) ◽  
pp. 694-702
Author(s):  
A S Goncharova ◽  
A N Shevchenko ◽  
I R Dashkova ◽  
A E Anisimov
Keyword(s):  
Cancer Biology ◽  
Malignant Neoplasms ◽  
Genetic Characteristics ◽  
Immunodeficient Mice ◽  
Advantages And Disadvantages ◽  
Patient Derived Xenograft ◽  
Therapeutic Algorithms ◽  
Incidence And Mortality ◽  
Xenograft Models ◽  
Methodological Aspects

High rates of cancer incidence and mortality from malignant neoplasms remains an urgent health problem. The development of the most effective therapeutic algorithms is required to improve the survival of cancer patients. An important condition for the discovery of new anticancer drugs and their translation into clinical practice involves the ability to model tumor growth, reproduce the characteristics of human disease, and evaluate measurable effects of pharmacological substances in laboratory facilities. Xenograft models established by direct implantation of fresh tumor tissue samples from individual patients into immunodeficient mice are considered suitable for both preclinical trials and for solving fundamental problems in oncology. The review highlights the significance of patient-derived xenograft models as a platform with high predictive value and the prerequisites that make them the preferred tool for research in cancer biology. The most important methodological aspects in the creation of these models are considered. Methods for obtaining and preparing biological tumor samples for xenotransplantation are discussed. The significance of the immune status, as well as the phenotypic and genetic characteristics of recipient animals, is described. The article presents the limitations of animal models associated with their immunodeficiency status and ways to overcome them. The principles for choosing xenotransplantation sites (heterotopic and orthotopic) and their advantages and disadvantages are discussed. In conclusion, we emphasize the need to continue the work on optimizing PDX (Patient-Derived Xenograft) models to overcome their limitations and to obtain the most reliable and valuable research results in oncology.

Impact and mechanistic role of MicroRNA-1291 on pancreatic tumorigenesis.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 243-243 ◽  
Author(s):  
Mei-Juan Tu ◽  
Yu-Zhuo Pan ◽  
Jing-Xin Qiu ◽  
Edward Jae-hoon Kim ◽  
Aiming Yu
Keyword(s):  
Cell Cycle ◽  
Cancer Biology ◽  
Critical Role ◽  
Experimental Studies ◽  
Mass Spectrometry Analysis ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Spectrometry Analysis

243 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Better understanding of pancreatic cancer biology and identification of new targets are highly warranted. MicroRNAs (miRs or miRNAs) play a critical role in the control of tumor progression via crosstalk with cancer signaling pathways. Our recent studies showed that miR-1291 improved chemosensitivity through targeting of efflux transporter ABCC1. This current study investigated the mechanistic role of miR-1291 in the suppression of pancreatic tumorigenesis. Methods: PANC-1 and AsPC-1 cell lines were stably transfected with miR-1291. Cell cycle status and apoptosis of stable miR-1291-expressing cells were tested against control cells using flow cytometry. Cells were injected subcutaneously into nude mice and tumorigenesis was measured in vivo. Proteomic studies were performed by two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. Computationally predicted miR-1291 targets were assessed by luciferase reporter assay and Western blot. Primary PDAC and control samples were tested for miR-1291 and target gene expression levels. Results: Our data showed that stable miR-1291-expressing PANC-1 and AsPC-1 cells both showed a significantly lower rate of proliferation than the control cells, which was associated with a cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 suppressed the tumorigenesis of PANC-1 cells in mouse models in vivo. Proteomic studies revealed the protein level of several cancer-related genes were downregulated by miR-1291, including a pancreatic tumor promoting protein AGR2 which was reduced ~10-fold. Through computational and experimental studies we further identified that FOXA2, a transcription factor governing AGR2 expression, was a direct target of miR-1291. In addition, we found a significant down-regulation of miR-1291 in a set of PDAC patient tumor samples overexpressing AGR2. Conclusions: These results indicate that miR-1291 suppresses pancreatic tumorigenesis via targeting of FOXA2-AGR regulatory pathway providing new insight supporting development of miR-1291-based therapy for PDAC.

Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with pancreatic ductal adenocarcinoma (PDA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4128-4128
Author(s):  
Nathan Bahary ◽  
Jie He ◽  
Mark Bailey ◽  
Shan Zhong ◽  
Gerald Li ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Clinical Care ◽  
Circulating Tumor Dna ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Genomic Profiling ◽  
Tissue Samples ◽  
Comprehensive Genomic Profiling ◽  
Cancer Genome Atlas ◽  
Genomic Characterization

4128 Background: PDA is a lethal and increasingly common malignancy and tissue samples for genomic characterization may be limited. As PDA has a high and consistent frequency of KRAS, p53 and CDKN2A mutations it serves as a robust indication to test the utility of ctDNA in accurately characterizing genomic alterations (GA). A prior study suggested significant differences between ctDNA and tissue base profiling but assays were not conducted on the same platform (PMID27833075). We undertook this study to see whether ctDNA could recapitulate the known genomic hallmarks of tumor based profiling. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 78 pts with advanced PDA with samples received in the course of clinical care. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Frequencies of alterations in these common drivers were then compared to those seen in tumors of pts who underwent comprehensive genomic profiling (CGP) tissue testing performed on the same core platform, FoundationOne, and The Cancer Genome Atlas (TCGA). Results: Pt characteristics: Median age 65 (range, 47-88); Female (33) /Male (45). FoundationACT results show that 53/78 (68%) cases had MSAF >0 (56%-78%%, 95% CI). ≥1 GA was reported in 81% of the cases with evidence of ctDNA in the blood. The most common GA detected by FoundationACT (based on cases with evidence of ctDNA in blood) vs FoundationOne were in KRAS (59% vs 89%, p< 0.0001), TP53 (69% vs.74%, p=0.19), and CDKN2A (14% vs.45%). Other detected clinically relevant GA detected by FoundationACT included: BRCA1, ERBB2, NF1, PIK3CA. Conclusions: This study demonstrates significant differences between the established driver oncogenic alterations for PDA, as assessed by ct DNA and tissue based genomic profiling which are unlikely to be explained by differences in assay, but rather novel cancer biology. At present use of ctDNA genomic profiling in PDA should not routinely replace tissue based genomic characterization. [Table: see text]

scholarly journals The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models

Oncogene ◽  
2015 ◽  
Vol 35 (7) ◽  
pp. 833-845 ◽  
Author(s):  
P L Garcia ◽  
A L Miller ◽  
K M Kreitzburg ◽  
L N Council ◽  
T L Gamblin ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Patient Derived Xenograft ◽  
Xenograft Models
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